This application is a request for continued funding of 2RO1 AI48793 for Years 11-15 of a rubella vaccine immunogenetics research program. Rubella remains an epidemic virus in much of the world, leading to fetal loss, malformation, congenital rubella syndrome, and current vaccines result in a failure rate of up to 5%. Our research is focused on identifying critical genetic determinates of immunity by examining associations between heterogeneity in humoral and cellular immune responses to rubella vaccine and gene polymorphisms. Importantly, our research demonstrates that humoral and cellular immune responses to rubella vaccine are significantly associated with HLA alleles and SNPs in candidate immune response genes, but these associations do not explain all of the variance in immune responses seen within the population. We will comprehensively identify the genetic determinants that explain our finding that the heritability of rubella vaccine-induced humoral immunity is nearly 50%. To do so, we propose a state-of-the-art genome-wide association study (GWAS) design, followed by replication studies in independent cohorts, and finally validation studies to determine the functional consequences of replicated SNPs. The data from our study will support a new vaccinomics Discover - Replicate - Validate - Apply paradigm for new vaccine development by defining how variations in rubella vaccine immune responses are determined by gene polymorphisms. To accomplish these goals, we propose the following Specific Aims: 1) Discover: To perform a GWAS to identify novel genetic associations between SNPs and multigenic interactions and markers of humoral (neutralizing antibody) and cell-mediated (IL-2, IL-6, IFN-3, TNF-1) immunity to rubella vaccine, 2) Replicate: To replicate a prioritized set of the strongest associations from both our GWAS and candidate gene SNPs from our currently funded grant in independent, population-based cohorts of subjects, and 3) Validate: To determine the direct effects and/or downstream functional consequences on immune outcomes of selected replicated genetic variants. This application is innovative and significant in that it will: examine the effect of gene polymorphisms on the heterogeneity of rubella vaccine immune responses, provide data that may explain mechanisms for these variations in rubella vaccine immune responses, provide data to support a novel paradigm of Discover - Replicate - Validate - Apply for new vaccine development. These studies will provide specific knowledge for understanding rubella immunity, and provide a model framework for estimating the genetic contribution on variations in immune responses to a viral vaccine. Lastly, our work may provide knowledge important to the development of new viral vaccines - particularly against rubella - by understanding genetic restrictions that prevent protective immune responses to vaccine.